The Dynamic Role of the Oxygen/TGFß Axis in Regulating Sphingolipid Metabolism during Placental Development

氧/TGFα轴在胎盘发育过程中调节鞘脂代谢的动态作用

• 批准号: RGPIN-2015-03906
• 负责人: Caniggia, Isabella
• 金额: $ 2.19万
• 依托单位: University of Toronto
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2018
• 资助国家: 加拿大
• 起止时间: 2018-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=646786
• 关键词: Dynamic; Role; Oxygen; TGF; Axis

***Changes in oxygen tension experienced by the growing placenta are crucial for proper development of the baby in the maternal womb and when a hypoxic environment persists beyond the first trimester of gestation, it consequently leads to inappropriate placental development and function. In the past decades, studies conducted in mouse have found that genetic manipulation of molecules that control oxygen homeostasis during pregnancy often leads to embryonic death and is frequently associated with striking abnormalities of the placenta. However, placental observations have been mostly descriptive and contribution of these genetic manipulations on placental cell death, an event required for proper growth of this organ, remains elusive. In this project we hypothesize that change in oxygen tension via activation of Transforming Growth Factor ß3 (TGFß3) regulate the metabolism of bioactive sphingolipids in the developing placenta. We propose an integrated approach utilizing relevant murine models and state-of-the-art lipidomic analyses to define the precise mechanism(s) of oxygen control of placental cell death and survival via bioactive sphingolipids. The long-term objective is to develop early diagnostic detectors as well as evidence-based intervention plans to prevent complication of pregnancy. The project is unique and innovative in many aspects: 1) No information is available on the oxygen-dependent mechanism(s) influencing the expression/function of sphingolipids in mouse pregnancy; in the current proposal we put forward a novel pathway of sphingolipid metabolism regulation. 2) We are also the first to examine the function of sphingolipids in the regulation of mouse placental cell fate, a research area that remains elusive. The proposed new methodological approaches to examine sphingolipid changes/function will not only advance the research field of pregnancy but also those of other research areas. Defining the controlling mechanisms of sphingolipid metabolism in the placenta will improve our understanding of oxygen signaling and regulation in the development of this organ and the well-being of the developing embryo. This may ultimately improve the management of pregnancy and prevent the risk of developing associated illnesses later in life both in mothers and their offspring. **

* 生长中的胎盘所经历的氧张力变化对于婴儿在母体子宫中的正常发育至关重要，当缺氧环境持续超过妊娠的前三个月时，它会导致胎盘发育和功能不适当。在过去的几十年里，在小鼠中进行的研究发现，对妊娠期间控制氧稳态的分子进行遗传操作通常会导致胚胎死亡，并且经常与胎盘的显著异常有关。然而，胎盘观察主要是描述性的，这些遗传操作对胎盘细胞死亡的贡献，这是该器官正常生长所需的事件，仍然难以捉摸。在这个项目中，我们假设通过转化生长因子β 3（TGF β 3）的活化来改变氧张力，从而调节发育中胎盘中生物活性鞘脂的代谢。我们提出了一种综合的方法，利用相关的小鼠模型和最先进的脂质组学分析，以定义通过生物活性鞘脂控制胎盘细胞死亡和存活的氧气的精确机制。长期目标是开发早期诊断检测器以及基于证据的干预计划，以预防妊娠并发症。该项目在许多方面具有独特性和创新性：1）没有关于影响鞘脂在小鼠妊娠中表达/功能的氧依赖性机制的信息;在本提案中，我们提出了一种新的鞘脂代谢调节途径。2)我们也是第一个研究鞘脂在调节小鼠胎盘细胞命运中的功能，这是一个仍然难以捉摸的研究领域。所提出的新的方法学方法来检查鞘脂的变化/功能，不仅将推进妊娠的研究领域，也将促进其他研究领域的研究。定义胎盘中鞘脂代谢的控制机制将提高我们对该器官发育中的氧信号和调节以及发育中胚胎的健康的理解。这可能最终改善妊娠管理，并防止母亲及其后代在以后的生活中患相关疾病的风险。**